Proteinuria, a pathognomonic sign of renal disease, is caused by increased protein filtration at the glomerulus or reduced protein uptake at the proximal tubule (PT). Protein uptake at the PT is mediated by the endocytosis and apical recycling of the scavenger receptors Megalin / Cubilin / Amnionless (MEG/CUB/AMN). Our current knowledge of these recycling processes is incomplete. Deeper understanding of these mechanisms is bound to lead to new therapies for proteinuric syndromes. The specific aims of this proposal are (1) to elucidate the endosomal pathways and molecular mechanisms responsible for MEG/CUB/AMN recycling and protein reabsorption in the kidney PT, (2) to study the cellular basis of genetic defects of the MEG/CUB/AMN system and (3) to search for drugs that block tubular uptake by MEG/CUB/AMN as a potential therapy for acute kidney failure caused by excessive internalization of immunoglobulin light chains and lysozyme in multiple myeloma and myelocytic leukemias. This project will allow the candidate to apply his strong background in intracellular trafficking to the study of an important problem in nephrology with focus on both basic and translational science. The detailed training plan includes hands-on training in various aspects of kidney research, courses on this subject, grant writing and translational research, regular attendance to nephrology meetings and seminars, participation in teaching activities and collaboration with kidney researchers and clinical nephrologists at WCMC. This training plan will allow the candidate (i) to develop a deep understanding of the literature on kidney patho/physiology, (ii) to acquire expertise in methods on kidney research and to publish impact papers in nephrology; (iii) to write an R01 proposal focused on the cellular basis of kidney patho/physiology, (iv) to develop a network in nephrology research; (vi) to identify job opportunities and to learn how to successfully apply for an independent faculty position. Together, the project and training plan should put him in an excellent position to pursue a career at the frontier of basic and translational kidney research.